Bicycloalkyl derivatives of prostaglandins PGE1 alcohols

ABSTRACT

Novel bicycloalkyl analogues or derivatives of prostaglandin A, E and F are useful modifiers of smooth muscle activity. The compounds have valuable pharmacological properties as platelet antiaggregating agents and gastric antisecretory agents. The compounds are also valuable pharmacological agents for increasing femoral blood flow and decreasing blood pressure and heart rate.

This is a division of application Ser. No. 657,221, filed Feb. 11, 1976now U.S. Pat. No. 4,074,063.

BACKGROUND OF THE INVENTION

1. Field of the Invention

Compounds of this invention are analogues of natural prostaglandins.

Natural prostaglandins are twenty-carbon atom alicyclic compoundsrelated to prostanoic acid which has the following structure: ##STR1##By convention, the carbon atoms of I are numbered sequentially from thecarboxylic carbon atom. An important stereo-chemical feature of I is thetrans-orientation of the side-chains C₁ -C₇ and C₁₃ -C₂₀. All naturalprostaglandins have this orientation. In I, as elsewhere in thisspecification, a dashed line ( ) indicates projection of a covalent bondbelow the plane of a reference carbon atom (alpha-configuration), whilea wedged line ( ) represents direction above that plane(beta-configuration). Those conventions apply to all compoundssubsequently discussed in this specification.

In one system of nomenclature suggested by N. A. Nelson (J. Med. Chem.,17: 911 (1972), prostaglandins are named as derivatives or modificationsof the natural prostaglandins. In a second system, the I.U.P.A.C.(International Union of Pure and Applied Chemistry) system ofnomenclature, prostaglandins are named as substituted heptanoic acids.Yet a third system of nomenclature is frequently used by those skilledin the prostaglandin art. In this third system (also described byNelson), all prostaglandins are named as derivatives or modifications ofprostanoic acid (structure I) or prestane (the hydrocarbon equivalent ofstructure I). This system is used by Chemical Abstracts and may becomean I.U.P.A.C. accepted system.

Natural prostaglandins have the structures, ##STR2## in which: L and Mmay be ethylene or cis-vinylene radicals and the five membered ring##STR3## may be: ##STR4##

Prostaglandins are classified according to the functional groups presentin the five-membered ring and the presence of double bonds in the ringor chains. Prostaglandins of the A-class (PGA or prostaglandin A) arecharacterized by an oxo group at C₉ and a double bond at C₁₀ -C₁₁(Δ¹⁰,11); those of the B-class (PGB) have an oxo group at C₉ and adouble bond at C₈ -C₁₂ (Δ⁸,12); compounds of the C-class (PGC) containan oxo group at C₉ and a double bond at C₁₁ -C₁₂ (Δ¹¹,12); members ofthe D-class (PGD) have an oxo group at C₁₁ and an alpha-oriented hydroxygroup at C₉ ; prostaglandins of the E-class (PGE) have an oxo group atC₉ and an alpha-oriented hydroxyl group at C₁₁ ; and members of theF-class (PGF) have an alpha-directed hydroxyl group at C₉ and analpha-oriented hydroxyl group at C₁₁. Within each of the A, B, C, D, E,and F classes of prostaglandins are three subclassifications based uponthe presence of double bonds in the side-chains at C₅ -C₆, C₁₃ -C₁₄, orC₁₇ -C₁₈. The presence of a trans-unsaturated bond only at C₁₃ -C₁₄ isindicated by the subscript numeral 1; thus, for example, PGE₁ (orprostaglandin E₁) denotes a prostaglandin of the E-type (oxo group at C₉and an alpha-hydroxyl at C₁₁) with a trans-double bond at C₁₃ -C₁₄. Thepresence of both a trans-double bond at C₁₃ -C₁₄ and a cis-double bondat C₅ -C₆ is denoted by the subscript numeral 2; for example, PGE₂.Lastly, a trans-double bond at C₁₃ -C₁₄, a cis-double bond at C₅ -C₆ anda cis-double bond at C₁₇ -C₁₈ is indicated by the subscript numeral 3;for example, PGE₃. The above notations apply to prostaglandins of the A,B, C, D, and F series as well, however, in the latter thealpha-orientation of the hydroxyl group at C₉ is indicated by thesubscript Greek letter α after the numerical subscript.

The three systems of nomenclature as they apply to natural PGF₃α areshown below: ##STR5## Nelson System:

Prostaglandin F₃α or PGF₃α (shorted form) I.U.P.A.C. System:

7-[3R,5S-Dihydroxy-2R-(3S-hydroxy-1E,5Z-octadienyl)cyclopent-1R-yl]-5Z-heptenoicacid

Third System (Chemical Abstracts):

(5Z, 9α, 11α, 13E, 15S,17Z)-9,11,15-trihydroxyprosta-5,13,17-trien-1-oic acid.

It is important to note that in all natural prostaglandins there is analpha-oriented hydroxyl group at C₁₅. In the Cahn-Ingold-Prelog systemof defining stereochemistry, that C₁₅ hydroxyl group is in theS-configuration. The Cahn-Ingold-Prelog system is used to definestereochemistry of any asymmetric center outside of the carbocyclic ringin all three systems of nomenclature described above. This is incontrast to some prostaglandin literature in which the α,β designationsare used, even at C₁₅.

11-Deoxy derivatives of PGE and PGF molecules do not occur as such innature, but constitute a class of compounds which possess biologicalactivity related to the parent compounds. Formula II represents 11-deoxyPGE and PGF compounds when: ##STR6## In this formula, and others of thispatent specification a swung dash or serpentine line (˜) denotes acovalent bond which can be either in the alpha configuration (projectingbelow the plane of a reference carbon atom) or in the beta configuration(projecting above the plane of a reference carbon atom).

PGF.sub.β molecules also do not occur as such in nature, but constitutea class of compounds which possess biological activity related to theparent compounds. Formula II represents PGF.sub.β compounds when:##STR7##

9-Deoxy derivatives of PGE do not occur as such in nature, butconstitute a class of compounds which possess biological activityrelated to the parent compounds. Formula II represents 9-deoxy PGEcompounds when: ##STR8##

9-Deoxy-Δ⁹,10 derivatives of PGE do not occur as such in nature, butconstitute a class of compounds which possess biological activityrelated to the parent compounds. Formula II represent 9-deoxy-Δ⁹,10 PGEcompounds when: ##STR9##

9-Homo- and 9α-homo-11-deoxy-derivative of PGE and PGF molecules do notoccur as such in nature, but constitute a class of compounds whichpossess biological activity related to the parent compounds. Formula IIrepresents 9α-homo- and 9α-homo-11-deoxy-compounds of PGE and PGF when:##STR10##

11-Homo-derivatives of PGE, PGF and PGA molecules do not occur as suchin nature, but constitute classes of compounds which are expected topossess biological activity related to the parent compounds. Formula IIrepresents 11α-homo-derivatives of PGE, PGF and PGA molecules when:##STR11##

11-Epi-PGE and PGF molecules do not occur as such in nature, butconstitute classes of compounds which possess biological activityrelated to the parent compounds. Formula II represents 11-epi-compoundsof PGE and PGF when: ##STR12##

8Iso-, 12iso or 8,12-bis iso (ent) prostaglandins do not occur as suchin nature, but constitute classes of compounds which possess biologicalactivity related to the parent compounds. Formula II represents 8iso-,12iso- or 8,12-bis iso (ent) compounds when: ##STR13## These isomodifications of Formula II may be divided into all of the sub-classeswith varying ring oxygenation as described above.

Recent research indicates that prostaglandins are ubiquitous in animaland that prostaglandins, as well as their synthetic analogues, haveimportant biochemical and physiological effects in mammalian endocrine,reproductive, central and peripheral nervous, sensory,gastro-intestinal, hematic, respiratory, cardiovascular, and renalsystems.

In mammalian endocrine systems, experimental evidence indicatesprostaglandins are involved in the control of hormone synthesis orrelease in hormone-secretory glands. In rats, for example, PGE₁ and PGE₂increase release of growth hormone while PGA₁ increased synthesis ofthat hormone. In sheep, PGE₁ and PGF₁α inhibit ovarian progesteronesecretion. In a variety of mammals, PGF₁α and PGF₂α act as luteolyticfactors. In mice, PGE₁, PGE₂, PGF₁α and PGF₁β increase thyroid activity.In hypophysectomized rats, PGE₁, PGE₂ and PGF₁α stimulatesteroidogenesis in the adrenal glands.

In the mammalian male reproductive system, PGE₁ contracts the smoothmuscle of the vas deferens. In the female reproductive system, PGE andPGF.sub.α compounds contract uterine smooth muscle. In general, PGE, PGBand PGA compounds relax in vitro human uterine muscle strips, whilethose of the PGF.sub.α class contract such isolated preparations. PGEcompounds in general promote fertility in the female reproductive systemwhile PGF₂α has contragestational effects. PGF₂α also appears to beinvolved in the mechanism of menstruation. In general, PGE₂ exertspotent oxytocic effects in inducing labor, while PGF₂α inducesspontaneous abortions in early pregnancy.

PGF.sub.α and PGE compounds have been isolated from a variety of nervoustissue and they seem to act as neurotransmitters. PGE₁ retards wherasPGF₂α facilitates transmission in motor pathways in the central nervoussystem. It has been reported that PGE₁ and PGE₂ inhibit transmitterrelease from adrenergic nerve endings in the guinea pig.

Prostaglandins stimulate contraction of gastrointestinal smooth musclein vivo and in vitro. In dogs, PGA₁, PGE₁ and PGE₂ inhibit gastricsecretion. PGA₁ exhibits similar activity in man.

In most mammalian respiratory tracts, compounds of the PGE and PGF classrelax in vitro preparations of tracheal smooth muscle. In thatpreparation, PGE₁ and PGE₂ relax while PGF₂α contracts the smoothmuscle. PGE and PGF compounds are normally found in the human lung, andit is postulated that some cases of bronchial asthma involve animbalance in the production or metabolism of these compounds.

Prostaglandins are involved in certain hematic mechanisms in mammals.PGE₁, for example, inhibits thrombogenesis in vitro through its effectson blood platelets.

In a variety of mammalian cardiovascular systems, compounds of the PGEand PGA class are vasodilators whereas those of the PGF.sub.α class arevasoconstrictors, by virtue of their action on vascular smooth muscle.

Prostaglandins are naturally found in the kidney and reverseexperimental and clinical renoprival hypertension.

The clinical implications of prostaglandins and their analogues arefar-ranging and include, but are not limited to the following: inobstetrics and gynecology, they may be useful in fertility control,treatment of menstrual disorders, induction of labor, and correction ofhormone disorders; in gastroenterology, they may be useful in thetreatment of peptic ulcers and various disorders involving motility,secretion, and absorption in the gastrointestinal tract; in therespiratory area, they may be beneficial in therapy of bronchial asthmaand other diseases involving bronchoconstriction; in hematology, theymay have utility as anti-clotting agents in diseases such as venousthrombosis, thrombotic coronary occlusion and other diseases involvingthrombi; in circulatory diseases they have therapeutic utility inhypertension, peripheral vasopathies, and cardiac disorders.

For a more complete review of chemical, physiological andpharmacological aspects of the prostaglandin, consult the followingreferences: The Prostaglandins, Vol. I., P. Ramwell, Ed., New York,Plenum Press, 1973; Ann. N.Y. Acad. Sci., 180: 1-568(1971): and Higginsand Braunwald, J. Am. Med. Assn., 53: 92-112(1972).

DESCRIPTION OF THE PRIOR ART

Great Britain Patent Application No. 027,844 filed June 14, 1971discloses cycloalkyl or adamantyl derivatives of prostaglandins.

Netherland Pat. No. 7,315,307 discloses cycloalkyl, adamantyl or2-norbornyl derivatives of prostaglandins.

SUMMARY

Novel and useful bicycloalkyl analogues of prostaglandins having thefollowing structural Formula III constitute the subject matter of thisinvention: ##STR14## In Formula III: g is an integer having a value offrom 0 to 10;

D is a R-hydroxymethylene or S-hydroxymethylene radical;

J is a methylene, R-hydroxymethylene, S-hydroxymethylene or a methineradical such that J is methine only when K is methine;

K is a methylene, ethylene or a methine radical such that K is ethyleneonly when J is methylene and K is methine only when J is methine to forma carbon-carbon double covalent bond between J and K;

L is a carbonyl, R-hydroxymethylene or S-hydroxymethylene radical;

Q is an ethylene or Z-vinylene radical;

T is an alkoxycarbonyl having from 1 to 3 carbon atoms inclusive in thealkyl chain, carboxyl, or hydroxymethyl radical or pharmacologicallyacceptable nontoxic carboxy salts; and

B is a bicycloalkyl radical of the formula ##STR15## where m and p areintegers having a value of from 1 to 4; n is an integer having a valueof from 0 to 4 such that n is not 1 when m and p are both 2; and the sumof m, n and p is greater than or equal to 3 and where the point ofattachment of the alkyl chain (CH₂)_(g) to the bicycloalkyl radical isin the (CH₂)_(m) bridge or bridgehead position.

The numbering system and the stereochemistry nomenclature used for theprostaglandins of this invention are according to the I.U.P.A.C.definitive and tentative rules which designate the carboxylic acid sidechain as the parent compound. In Formula III, a swung dash or serpentiveline (˜) denotes a covalent bond which can be either in the alphaconfiguration (projecting below the plane of a reference carbon atom) orin the beta configuration (projecting above the plane of a referencecarbon atom). As used herein, cis or trans isomerism around double bondsrespectively is designated by affixes Z (zusammen) and E (entgegen).Chirality around asymmetric carbon atoms is designated by affixes R(rectus) and S (sinister).

Analogues or derivatives of the A-, E-, and F- classes of the naturalprostaglandins are represented by Formula III. Thus when, L is carbonyl,and both J and K are methine radicals, III represents analoges of the A-class of prostaglandins: ##STR16##

When L is carbonyl, K is methylene or ethylene and J is methylene orhydroxymethylene such that K is ethylene only when J is methylene, IIIrepresents analogues of the E-class, 11-deoxy-E- class or9a-homo-11-deoxy-E-class of prostaglandins: ##STR17##

When L is carbonyl, K is methylene and J is R-hydroxymethylene orS-hydromethylene, III represents analogues of the E-class ofprostaglandins: ##STR18##

When L is carbonyl and both J and K are methylene, III representsanalogues of the 11-deoxy-E-class of prostaglandin: ##STR19##

When Q is Z-vinylene, L is carbonyl, K is ethylene and J is methylene,III represents analogues of 9a- omo-11-deoxy-PGE₂ : ##STR20##

When L is R-hydroxymethylene or S-hydroxymethylene; K is methylene orethylene; J is R-hydroxymethylene, S-hydroxymethylene or methylene suchthat K is ethylene only when J is methylene, III represents analogues ofPGF₃, PGF.sub.β, 11-deoxy-F.sub.α, 11-deoxy-F.sub.β, 9a-homo-11-deoxyF.sub.α and 9a-homo-11-deoxy F.sub.β : ##STR21##

When L is R-hydroxymethylene or S-hydroxymethylene; K is methylene; andJ is R-hydroxymethylene or S-hydroxymethylene, III represents analoguesof PGF.sub.α and PGE.sub.β : ##STR22##

Useful intermediates in the preparation of compounds of Formula III arerepresented by the formula: ##STR23## wherein:

X is an iodo or bromo radical;

A is an acid-labile protecting group selected from the class consistingof 1-ethoxyethylene, trimethylsilyl, tert-butyl-dimethylsilyl,2-ethoxy-prop-2-yl, triphenylmethyl, or tetrahydropyran-2-yl radicals;

g is an integer having a value of from 0 to 10; and

B is selected from the class of bicycloalkyl radicals of the formula:##STR24## where m and p are integers having a value of from 1 to 4; n isan integer having a value of from 0 to 4 such that the sum of m, n and pis greater than or equal to 3 and the point of attachment of the alkylchain (CH₂)_(g) to the bicycloalkyl radical is in the (CH₂)_(m) bridgeor in the bridgehead position.

Other useful intermediates in the preparation of compounds of FormulaIII are represented by the formula: ##STR25## wherein:

A is an acid-labile hydroxyl-protecting group selected from the classconsisting of 1-ethoxyethylene, trimethylsilyl,tert-butyl-dimethylsilyl, 2-ethoxy-prop-2-yl, triphenyl methyl, ortetrahydropyran-2-yl radicals;

Q is an ethylene or Z-vinylene radical; and

J' is a R-hydroxymethylene radical protected with an acid-labilehydroxyl-protecting group A.

Another useful intermediatein the preparation of compounds of FormulaIII is methyl 7-(6-oxocyclohex-1-enyl) hept-5Z-enoate.

DESCRIPTION OF THE INVENTION

Compounds having Formula III are prepared via the 1,4-conjugate additionof organocopper reagents to cyclopentenones as reported by Sih, et. al.,(J.Amer. Chem. Soc., 97: 857,865 (1975) and references cited therein).The novel compounds of Formula III are prepared according to thereaction sequence depicted in Table A.

                                      TABLE A                                     __________________________________________________________________________     ##STR26##                                                                     ##STR27##                                                                     ##STR28##                                                                    __________________________________________________________________________

In Table A, Compound IV, where X is an iodo or bromo radical and A is anacid-labile hydroxyl-protecting group, is contacted and reacted withmetallic lithium or a lower alkyl lithium (Compound V) at from about-80° C to 0° C for about 0.25 to 3.0 hours in an inert solvent, such asether, tetrahydrofuran, hexane., pentane, toluene, mixtures thereof andthe like, under an inert atmosphere, such as argon, nitrogen and thelike. Copper(I) complex (Compound VI) is added, usually as a solution inan inert solvent, to the reaction mixture and the mixture is thenstirred at less than about -20° C for about 0.25 to 1.0 hour. A solutionof Compound VII, where J' is methylene or ═CHOA and T' is alkoxycarbonylor --CH₂ OA, usually in an inert solvent, is added to the reactionmixture which is then allowed to warm to about -20° C to 25° C over a0.5 to 5 hour period to yield the intermediate Compound VIII afterquenching with a proton donor. Treatment of the latter compound underhydrolysis conditions such as with a weakly-acidic water mixture, suchas acetic acid-water (65:35 V/V) with 10% tetrahydrofuran, under aninert atmosphere at a temperature of about 20° C to 45° C for about 0.5to 48 hours cleaves the acid-labile hydroxyl-protecting groups(described in J. Amer. Chem. Soc., 94:6194[1972]) to yield CompoundIIIb.

Where J and K of Compound IIIb are respectively hydroxymethylene andmethylene, dehydration of Compound IIIb with a weakly-acidic watermixture, such as acetic acid-water, at about 60° C to 80° C (describedin J. Org. Chem., 34:3552 [1969]) yields Compound IIIa, Compound IIIa isalso obtained as a byproduct of the acidic hydrolysis of Compound VIII.

Reduction of Compound IIIb with sodium borohydride in an inert alcoholicor other suitable polar solvent (described in J. Org. Chem.,34:3552[1969]) yields Compound IIIf.

When T of Compound IIIb (where J is methylene or IIIf is alkoxycarbonyl,cleavage of the ester group with a base, such as sodium hydroxide orpotassium hydroxide in a mixed organic solvent such aswater-tetrahydrofuran, water-p-dioxane or water-alcohol described in J.Amer. Chem. Soc., 94:7823 [1973]) yields the corresponding acid, i.e.where T is carboxyl. Where J and T of Compound IIIb are respectivelyhydroxymethylene and alkoxycarbonyl, cleavage of the ester group byexposure to Rhizopus oryzae (described in J. Amer. Chem. Soc.95:1676[1973]) or with a suitable esterase or lipase (described inU.S.P.N. 3,769,166 and German Patent Application No. 2,242,792) yieldsthe corresponding acid, i.e. where T is carboxyl.

Where T of Compounds IIIa, IIIb or IIIf is a carboxyl or alkoxycarbonylgroup, reduction of the carboxyl or ester group, after treatment with acarboxyl protecting group, followed by treatment with nitrous acidyields the corresponding primary alcohol, ie. where T is hydroxymethyl(described in U.S. Pat. No. 3,636,120). Suitable carboxyl protectinggroups include lower alkoxyamines, semicarbazides or thiosemicarbazides.Suitable reducing agents include lithium aluminum hydride, lithiumborohydride, or diisobutyl aluminum hydride.

Non-toxic, pharmacologically acceptable salts of Compound III can beprepared by neutralization of III, where T is carboxyl, with anequivalent or an excess amount of the corresponding non-toxicsalt-forming organic or inorganic base. The salts are prepared byprocedures which are well-known in the art. Suitable salts includesodium, potassium, ammonium and the like. The salts may be isolated bylyophilization of the resulting mixture, or by filtration, ifsufficiently insoluble, or by similar well-known techniques.

All compounds of this invention can be isolated from reaction mixturesand purified by well-known organic chemistry procedures. For example,the compounds can be isolated by dilution of the reaction mixture withwater, extraction with a water-immiscible solvent such as benzene,cyclohexane, ether, ethyl acetate, methylene chloride, toluene and thelike; chromatography; distillation or a combination of these procedures.Purification of these compounds can be accomplished by methods which arewell-known in the art for the purification of prostaglandins, lipids,fatty acids, and fatty esters. For example, such methods as reversephase partition chromatography; counter-current distribution; adsorptionchromatography on acid washed magnesium silicate, neutral or acid washedsilica gel, alumina or silicic acid; preparative paper chromatography;preparative thin layer chromatography; high pressure liquid-liquidchromatography; gas-liquid chromatography; and combinations thereof canbe used to purify the compounds produced by the processes of thisinvention.

The starting reactants used in the above procedures are well-known oreasily prepared by known methods. For instance, in the reaction sequencedepicted in Table A, Compound V, i.e. metallic lithium or lower alkyllithium such as t-butyllithium, sec-butyllithium or n-butyllithium arecommercially available or prepared by well-known organic chemistrymethods. Examples of Compound VI, i.e. copper(I) complexes, include:[hexamethylphosphorous triamide]₂ copper(I) pentyne (preparationdescribed in J. Amer. Chem. Soc., 94:7210[1972]; and J. Org. Chem.,31:4071[1966]); tri-n-butylphosphine-copper(I) iodide (preparationdescribed in Inorg. Synth., 7:9]1963]); hexamethylphosphoroustriamide-copper(I) iodide (preparation described in Prostaglandins,7:387[1974]); copper(I) thiophenolate (preparation described inSynthesis, 662[1974]) and the like. Examples of Compound VII which areemployed in the synthesis of III include: methyl7-(5-oxocyclopent-1-enyl)heptanoate (preparation described in Tet. Let.,24:2435[1972]); methyl7-[3R-(tetrahydropyran-2-yloxy)-5-oxocyclopent-1-enyl]heptanoate(preparation described in J. Amer. Chem. Soc., 95:1676[1973]);1-(tetrahydropyran-2-yloxy)-7-(5-oxocyclopent-1-enyl)heptane(preparation described in Tet. Let., 773[1972]); Methyl7-(5-oxocyclopent-1-enyl)hept-5Z-enoate (preparation described in J.Org. Chem., 38:3413[1973]); Methyl 7-[3R-(tetrahydropyran-2-yloxy)-5-oxocyclopent-1-enyl]hept-5Z-enoate (preparation described inTet. Let., 2313[1973]); Methyl 7-(6-oxocyclohex-1-enyl)hept-5Z-enoate(preparation of this novel compound is described in Example 13);1-(tetrahydropyran-2-yloxy(-7-[3R-(tetrahydropyran-2-yloxy)-5-oxocyclopent-1-enyl]heptane(TR-C7E1).; and1-(tetrahydropyran-2-yloxy)-7-[3R-(tetrahydropyran-2-yloxy)-5-oxocyclopent-1-enyl]hept-5Z-ene(TR-C7E2).

Compounds TR-C7E1 and TR-C7E2, disclosed above, are novel intermediatesuseful in the preparation of prostaglandin analogues of the E₁ and E₂classes where T is a hydroxymethyl radical in Formula IIIc. CompoundsTR-C7E1 and TR-C7E2 can be prepared from well-known materials by thefollowing reaction scheme: r1 ? ##STR29## wherein J is aR-hydroxymethylene radical; Q is an ethylene or Z-vinylene radical; T isan alkoxycarbonyl, having from 1 to 3 carbon atoms inclusive in thealkyl chain, or carboxyl radical; A is an acid-labilehydroxyl-protecting group; and J' is an R-hydroxymethylene radicalprotected with an acid-labile hydroxyl-protecting group A. In IX → X,Compound IX is reacted with hydroxylamine to form the correspondingoxime-protected carbonyl, Compound X, using conditions which arewell-known in the art (see U.S. Pat. No. 3,636,120 and Australian PatentNo. 5,108,173). In X → XI, Compound X is reacted with a suitablereducing agent such as lithium aluminum hydride, lithium borohydride,diisobutyl aluminum hydride and the like, at a temperature below about30° C. to reduce the ester or carboxyl group at T to the correspondingalcohol, Compound XI (where T is hydroxymethyl). In XI → XII, CompoundXI is reacted with nitrous acid at a temperature of about -10° C toabout 50° C to remove the oxime protecting group and regenerate thecarbonyl. The nitrous acid is formed by adding an aqueous solution of analkali metal or alkaline earth metal nitrite, such as sodium nitrite, toa liquid alkanoic acid such as acetic or propionic acid. In XII → VII,Compound XII is reacted with a suitable acid-labile hydroxyl-protectinggroups (A) such as dihydropyran or ethylvinyl ether in the presence ofan acid catalyst such as p-toluensulfonic acid, 98% sulfuric acid orphosphorus oxychloride to form Compound VII and the product is isolatedby standard procedures.

Compound IV of Table A is prepared according to the reaction sequencedepicted in Table B. Examples of compounds having Formula IV which areused in the reaction IV → III include:1-iodo-3-(1-ethoxyethoxy)-3-(bicyclo[3.2.0]hept-3-yl)-1E-propene;1-iodo-3-(1-ethoxyethoxy)-7-(bicyclo[3.2.1]oct-2-yl)-1E-heptene;1-iodo-3-(1-ethoxyethoxy)-7-(bicyclo[4.4.0]dec 2-yl)-1E-heptene and1-iodo-3-(1-ethoxyethoxy)-4-(bicyclo[2.2.1]hept-2-yl)-1E-butene. Thesynthesis of Compound IV from the corresponding bicycloalkyl acid IVacan be accomplished via the reaction sequence of Table B by well-knownorganic chemistry procedures.

                  TABLE B                                                         ______________________________________                                         ##STR30##                   (IVa)                                             ##STR31##                   (IVb)                                             ##STR32##                   (IVc)                                             ##STR33##                   (IVd)                                             ##STR34##                   (IVe)                                             ##STR35##                   (IV)                                             ______________________________________                                    

In IVa → IVb, the bicycloalkyl acid IVa is converted to the acidchloride IVb using an acid chloride forming reagent such as thionylchloride, oxalyl chloride, phosphorus trichloride and the like asdescribed in Fieser & Fieser, Reagents For Organic Synthesis, I: 1158,J. Wiley & Sons Inc. (1967). In IVb → IVc, the acid chloride IVb isreacted with acetylene in an inert solvent, such as carbontetrachloride, methylene chloride or the like, in the presence of aLewis acid such as aluminum chloride, stannic chloride or the like toproduce the β-chlorovinyl ketone IVc as described in Chem. Rev.,161(1965) and Org. Synth., IV:186, J. Wiley & Sons Inc. (1963). In IVc →IVc, the β-chlorovinyl ketone IVc is converted into the correspondingβ-iodo- or β-bromo-vinyl ketone IVd, where X is an iodo or bromoradical, using a soluble salt, such as sodium iodide, sodium bromide,lithium bromide or the like, in a polar inert solvent, such as acetone,acetonitrile or the like, as described in J. Amer. Chem. Soc.,94:7210(1972). In IVd → IVe, Compound IVd is reduced to thecorresponding β-iodo- or β-bromo-vinyl alcohol using a suitable reducingagent, such as sodium borohydride in alcohol solvent or lithium aluminumhydride in ether solvent as described in J. Amer. Chem. Soc.,94:7210(1972). In IVe → IV, Compound IVe is contacted and reacted with asuitable hydroxyl-protecting agent (A) such as dihydropyran orethylvinyl ether in the presence of an acid catalyst such asp-toluenesulfonic acid, 98% sulfuric acid or phosphorus oxychloride; ora trialkylsilylchloride, such as trimethylsilylchloride ort-butyldimethysilylchloride, or triphenylmethylbromide in the presenceof a basic catalyst such as triethylamine or imidazole. Any hydroxylprotecting group that is removable under mildly acid conditions and isstable to alkyllithium and alkylcopper(I) reagents can also be suitablyused, see J. Org. Chem. 37:1947(1972).

Examples of the corresponding bicycloalkyl carboxylic acids havingFormula IVa include: bicyclo[3.2.0]heptane-3-carboxylic acid;5-(bicyclo[3.2.1]oct-2-yl)pentanoic acid;5-(bicyclo[4.4.0]dec-2-yl)pentanoic acid; and(bicyclo[2.2.1]hept-2-yl)acetic acid. The bicycloalkyl carboxylic acidsof Formula IVa are either commercially available or are prepared bywell-known techniques from commercially available materials. Forexample, the Compound cis-1,2-cyclobutanedicarboxylic anhydride isreduced with a suitable reagent, such as lithium aluminum hydride,lithium borohydride, lithium tri-t-butoxyaluminum hydride or borane, toproduce cis-1,2-bis(hydroxymethyl)cyclobutane. This latter compound isthen substituted for trans-1,2-bis-(hydroxymethyl)cyclobutane in theprocedure described in J. Org. Chem., 29:2914 (1964) for the preparationof trans-(bicyclo[3.2.0]hept-3-yl)carboxylic acid. The product of thisprocedure is thus cis-(bicyclo[3.2.0]hept-3-yl)carboxylic acid. Thislatter compound is used in the reaction sequence depicted in Table B toproduce1-iodo-3-(1-ethoxyethoxy)-3-(bicyclo[3.2.0]hept-3-yl)-1E-propene.

Other commercially available cis or trans isomers of1,2-dicarboxycycloalkyl; 1,2-bis(hydroxymethyl)cycloalkyl; or1,2-bis(bromomethyl)cycloalkyl may be used in the above procedure toproduce compounds of structure IVa where g is O and B is ##STR36## Theselatter compounds lead to prostaglandins of structure III in which g is0, m is 3, n is 0 and p is 1 to 4.

5-(Bicyclc[3.2.1]oct-2-yl)pentanoic acid is prepared by the followingprocedure. The compound 2-oxobicyclo[3.2.1]octane is reacted with asuitable base, such as sodium hydride, potassium hydride, lithiumhydride, lithium diisopropylamide, or lithium t-butoxide, and(4-carboxybutyl)triphenyl phosphonium bromide in an inert solvent suchas dimethylsulfoxide, benzene, diethylether, t-butanol or mixturesthereof, via a Wittig reaction (Tet. Let., 4:311 [ 1970],) to producethe intermediate compound 5-(bicyclo[3.2.1]oct-2-ylidene)pentanoic acid.This latter compound is catalytically reduced in a suitable solvent suchas ethanol, other alcohols or organic acids in the presence of ahydrogenation catalyst such as platinum oxide, Pd on carbon, RuO₂, orRa-Ni and a reducing agent such as hydrogen, diimide or the like toproduce 5-(bicyclo[3.2.1]oct-2-yl)pentanoic acid. This latter compoundis used in the reaction sequence depicted in Table B to produce1-iodo-3-(1-ethoxyethoxy)-7-(bicyclo[3.2.1]oct-2-yl)-1E-heptene.

Other commercially available or easily prepared oxobicyclo[m.n.p]alkanescan be used in place of 2-oxobicyclo[3.2.1] octane in the Wittigreaction to yield a variety of 5-(bicyclo[m.n.p.]alkylidene) pentanoicacids which can then be used in the synthesis of a variety ofprostaglandins with structure III. For example, cis or trans(bicyclo[4.4.0] decan-1-one) may be used in the above Wittig reactionfollowed by reduction to produce1-iodo-3-(1-ethoxyethoxy)-7-bicyclo[4.4.0] dec-2-yl)-1E-heptene.

Easily prepared (ω-carboxylkyl) triphenyl phosphonium bromide reagentsmay be used in place of (4-carboxybutyl) triphenyl phosphonium bromidein the Wittig reaction to yield ω-(bicyclo[ m.n.p.] alkylidene) alkanoicacids which can then be used in the synthesis of prostaglandins withStructure III. The (ω-carboxyalkyl)triphenyl phosphonium bromidereagents are most easily prepared by reacting triphenylphosphine with anω-bromoalkanoic acid in an inert solvent such as benzene, acetonitrile,ether or the like, usually at an elevated temperature, such as solventreflux. The products are usually isolated as crystalline salts whichseparate from the reaction mixture upon cooling.

The compounds represented by Formula III inhibit aggregation of humanplatelets in vitro as demostrated in the following Example 14. It isthat feature which distinguishes the compounds of this invention overthe natural prostaglandins. Of the natural prostaglandins, only PGE₁displays a similar activity. The protaglandin analogues of thisinvention also stimulate in vitro and in vivo smooth muscle preparationsderived from a variety of tissues and organs of experimental animals.Such smooth muscle assays are widely utilized to determine the activityof natural prostaglandins as well as prostaglandin analogues (Bundy etal., Ann. N.Y. Acad. Sci., 180:76[1961]; Bergstrom et al., Pharmacol.Revs., 20:1[1968]). Details of the activity of certain compounds havingFormula III are presented in Example 14 below.

The following Table C illustrates preferred embodiments of the presentinvention compiled by Compound No., Example No. and identified by boththe I.U.P.A.C. and Nelson systems of nomenclature.

                                      TABLE C                                     __________________________________________________________________________    Compound                                                                            Ex.                                                                     No.   No.                                                                              IUPAC Nomenclature        Nelson System                              __________________________________________________________________________    TR-4118                                                                             2D methyl 7-{5-oxo-2R-[3S-hydroxy-7-(bicyclo-                                                              19-(bicyclo[3.2.1]oct-2-yl)-20-norprost                                       a-                                                  [3.2.1]oct-2-yl)-1E-heptenyl]cyclopent-                                                                 glandin A.sub.1 methyl ester                        3-en-1R-yl}heptanoate.                                               TR-4119                                                                             2C methyl 7-{5-oxo-2R-[3R-hydroxy-7-(bicyclo-                                                              15-epi-19-[bicyclo[3.2.1 oct-2-yl)-20-                                        .                                                   [3.2.1]oct-2-yl)-1E-hepentyl]cyclopent-3-                                                               norprostaglandin A.sub.1 methyl ester               en-1R-yl}heptanoate.                                                 TR-4098                                                                             1A methyl 7-{3R-hydroxy-5-oxo-2R-[3R-hydroxy-                                                              15-(bicyclo[3.2.0]hept-3-yl)-16,17,18,1                                       9,-                                                 3-(bicyclo[3.2.0]hept-3-yl)-1E-propenyl]-                                                               20-pentanor prostaglandin E.sub.1                                             methyl ester                                        cyclopent-1R-yl]heptanoate.                                          TR-4099                                                                             1B methyl 7-{3R-hydroxy-5-oxo-2R-[2S-hydroxy-                                                              15-epi-15-(bicyclo[3.2.0]hept-3-yl)-16,                                       17,-                                       3-(bicyclo[3.2.0]hept-3-yl)-1E-propenyl]-                                           18,19,20-pentanor prostaglandin E.sub.1 methyl                                   cyclopent-1R-yl)heptanoae.                                           TR-4117                                                                             2A methyl 7-{3R-hydroxy-5-oxo-2R-[3S-hydoxy-                                                               19(bicyclo[3.2.1]oct-2-6l)-20-norprosta                                       -                                                   7-(bicyclo[3.2.1]oct-2-yl)-1E-heptenyl]-                                                                glandin E.sub.1 methyl ester                        cyclopent-1R-yl}heptanoate.                                          TR-4116                                                                             2B methyl 7-{3R-hydroxy-5-oxo-2R-[3R-hydroxy-                                                              15-epi-19-(bicyclo[3.2.1]oct-2-yl)-20-                                        O                                                   7-(bicyclo[3.2.1]oct-2-yl)-1E-heptenyl]-                                                                norprostaglandin E.sub.1 methyl ester                                         N                                                   cyclopent-1R-yl}heptanoate.                                          TR-4172                                                                             2E methyl 7-{3R-hydroxy-5-oxo-2R-[3S-                                                                      19-(bicyclo[4.4.0]dec-2-yl)-20-norprost                                       a-                                                  hydroxy-8-(bicyclo[4.4.0]dec-2-yl)-1E-                                                                  glandin E.sub.1 methyl ester                        heptenyl[cyclopent-1R-yl}heptanoate.                                 TR-4166                                                                             2F methyl 7-55 3R-hydroxy-5-oxo-2R-[3R-                                                                    15-epi-19-(bicyclo[4.4.0]dec-2-yl)-20-              hydroxy-7-{3R-hydroxy-5-oxo-2R-[3R-                                                                     15-epi-19-(bicyclo[4.4.0]dec-2-yl)-20-                                        N                                                   hydroxy-7-(bicyclo[4.4.0]dec.-2-yl)-1E-                                                                 norprostaglandin E.sub.1 methyl ester               heptenyl]cyclopent-1R-yl}heptanoate.                                 TR-4643                                                                             3A 7-{3R-hydroxy-5-oxo 2R-[3S-hydroxy-3-                                                                   15-epi-15-(bicyclo[3.2.0]hept-3-yl)-2-d                                       ecar-                                               (bicyclo[3.2.0]hept-3-yl)-1E-propenyl]-                                                                 boxy-2-hydroxymethyl-16,17,18,19,20-                cyclopent-1R-yl}heptan-1-ol.                                                                            pentanorprostagland E.sub.1                TR-4642                                                                             3B 7-{3R-hydroxy-5-oxo-2R-[3R-hydroxy-3-                                                                   15-(bicyclo[3.2.0]hept-3-yl)-2-decarbox                                       y-2-                                                (bicyclo[3.2.0]hept-3-yl)-1E-propenyl]-                                                                 hydroxymethyl-16,17,18,19,20-pentanorpr                                       osta-                                               cyclopent-1R-yl}heptan-1-ol.                                                                            glandin E.sub.1                            TR-4097                                                                             4A dl-7-{5-oxo-2R-[3S-hydroxy-3-(bicyclo-                                                                  (+)-11-deoxy-15-epi-15-(bicyclo[3.2.0]h                                       ept-3-                                              [3.2.0]hept-3-yl)-1E-propenyl]cyclopent-                                                                yl)-16,17,18,19,20-pentanorprostaglandi                                       n E.sub.1                                           1R-yl}heptanoic acid.                                                TR-4096                                                                             4B dl-7-{5-oxo-2R[3R-hydroxy-3-(bicyclo-                                                                   (+)-11-deoxy-15-(bicyclo[3.2.0]hept-3-y                                       l)-                                                 [3.2.0]hept-3-yl)-1E-propenyl[cyclopent-                                                                16,17,18,19,20-pentanoprostaglandin                                           E.sub.1                                             1R-yl}heptanoic acid.                                                TR-4189                                                                             5A dl-7-{5-oxo-2R[3S-hydroxy-7-(bicyclo-                                                                   (+)-11-deoxy-19-(bicyclo[4.4.0]dec-2-yl                                       )-20-                                               [4.4.0]dec-2-yl)-1E-heptenyl]cyclopent-                                                                 norprostaglandin E.sub.1                            1R-yl}heptanoic acid.                                                TR-4190                                                                             5B dl-7-{5-oxo-2R-[3R-hydroxy-7-(bicyclo-                                                                  (+)-11-deoxy-15-epi-19-(bicyclo[4.4.0]d                                       ec-2-                                               [4.4.0]dec-2-yl)-1E-heptenyl]cyclopent-                                                                 yl)-20-norprostaglandin E.sub.1                     1R-yl}heptanoic acid.                                                TR-4101                                                                             6A dl-7-{5-oxo-2R[3R-hydroxy-2-(bicyclo-                                                                   (+)-11-deoxy-15-(bicyclo[3.2.0]hept-3-y                                       l)-                                                 [3.2.0]hept-3-yl)-1E-propenyl]cyclopent-                                                                16,17,18,19,20-pentanorprostaglandin                                          E.sub.2                                    TR-4102                                                                             6B dl-7-{5-oxo-2R-[ 8 3S-hydroxy-3-(bicyclo-                                                               (+)-11-deoxy-15-epi-15-(bicyclo[3.2.0]h                                       ept-                                                [3.2.0]hept-3-yl)-1E-propenyl]cyclopent-                                                                3-yl)-16,17,18,19,20-pentanorprostaglan                                       din                                                 1R-yl}hept-5Z-enoic acid. E.sub.2                                    TR-4173                                                                             6C dl-7-{5-oxo-2R-[3R-hydroxy-7-(bicyclo-                                                                  (+)-11-deoxy-19-(bicyclo[4.4.0]dec-2-yl                                       )-20-                                               [4.4.0]dec-2-yl)-1E-heptenyl]cyclopent-                                                                 norprostaglandin E.sub.2                            1R-yl}hept-5Z-enoic acid.                                            TR-4174                                                                             6D dl-7-{5-oxo-2R-[3R-hydroxy-7-(bicyclo-                                                                  (+)-11-deoxy-15-epi-19-(bicyclo[4.4.0]d                                       ec-                                                 [4.4.0]dec-2-yl)-1E-heptenyl]cyclopent-                                                                 2-yl)-20-norprostaglandin E.sub.2                   1R-yl}-hept-5Z-enoic acid.                                           TR-VIIa                                                                             7A dl-7-{6-oxo-2R-[3S-hydroxy-7-(bicyclo-                                                                  (+)-11-deoxy-19-(bicyclo[4.4.0]dec-2-yl                                       )-                                                  [4.4.0]dec-2-yl)-1E-heptenyl]cyclohex-1R-                                                               9a-homo-20-norprostaglandin E.sub.2                 yl}hept-5Z-enoic acid.                                               TR-VIIb                                                                             7B dl-7-{6-oxo-2R-[3R-hydroxy-7-(bicyclo-                                                                  (+)-11-deoxy-15-epi-19-(bicyclo[4.4.0]d                                       ec-                                                 [4.4.0[dec-2-yl)-1E-heptenyl]cyclohex-                                                                  2-yl)-9a-homo-20-norprostaglandin                                             E.sub.2                                             1R-yl}hept-5Z-enoic acid.                                            TR-4712                                                                             8A methyl 7-{3R,5R-dihydroxy-2R-[3S-hydroxy-                                                               15-epi-15-(bicyclo[3.2.0]hept-3-yl)-16,                                       17,-                                                3-(bicyclo[3.2.0]hept-3-yl)-1E-propenyl]-                                                               18,19,20-pentanorprostaglandin                                                F.sub.1β methyl                                cyclopent-1R-yl}heptanoate.                                                                             ester                                      TR-4711                                                                             8B methyl 7-{3R, 5S-dihydroxy-2R-[3S-hydroxy-                                                              15-epi-15-(bicyclo[3.2.0]hept-3-yl)-16,                                       17,-                                                3-(bicyclo[3.2.0]hept-3-yl)-1E-propenyl]-                                                               18,19,20-pentanorprostaglandin                                                F.sub.1α methyl                               cyclopent-1R-yl}heptanoate.                                                                             ester                                      __________________________________________________________________________

In order to further illustrate the novel aspects of the presentinvention, the following examples are presented. It should be recognizedthat these examples are provided by way of illustration only and are notintended to limit in any way the invention disclosed herein. Compoundsidentified by compound number in the following examples refer to thecompounds as compiled in Tablc C.

EXAMPLE 1

This example illustrates a typical preparation of Prostaglandin E₁Analogues.

Compounds TR-4098 and TR-4099 were prepared according to the procedurewhich follows. A mixture containing 940 mg (3.14 mmol) of1-iodo-3-(1-ethoxyethoxy)-3-(bicyclo[3.2.0]hept-3-yl)-1E-propene (seeExample 11) dissolved in 180 ml of ether was prepared, cooled to -78° C,and stirred under an argon atmosphere. Then 3.38 ml of 1.7Nt-butyllithium in n-pentane was added and the mixture was stirred at atemperature of -78° C for 2 hr. A solution of 328 mg of copper(I)pentyne and 0.9 ml hexamethyl phosphorous triamide in 10 ml ether wasadded to the reaction flask with stirring at -78° C. The resultingmixture was stirred 40 min at -78° C, and 714 mg (2.20 mmol) of methyl7-[3R-tetrahydropyran-2-yloxy)-5-oxocyclopent-1-enyl]heptanoate in 6.0ml of ether was added thereto. The mixture was stirred for 35 min at-78° C and subsequently brought to -10° C and stirred for 1.5 hr. Themixture was stirred for 0.5 hr at 0° C and an additional 0.5 hr at 25°C. The mixture was quenched by the addition of 20% aqueous ammoniumsulfate and extracted with ether. The ether extract was shakensuccessively with 2% (v/v) sulfuric acid, saturated aqueous NaHCO₃,saturated aqueous NaCl, then dried over MgSO₄, filtered throughdiatomaceous earth and the solvents removed in vacuo to yield 1.40 g ofa yellow oil. The resulting oil was stirred with 27.0 ml of 65:35 aceticacid-water and 2.7 ml of tetrahydrofuran for 15 hr at 25° C. Thesolvents were removed in vacuo and the residue was mixed with water andextracted several times with ether. The ether extracts were washed withaqueous sodium bicarbonate and then aqueous saturated NaCl. The washedether extracts were then dried over MgSO₄ and evaporated in vacuo toyield 1.30 g of a yellow oil. The oil was column chromatographed usingan 85:15 silicic acid:diatomaceous earth (Celite) support and using abenzene to ethyl acetate gradient elution to yield 126.4 mg of CompoundTR-4098 and 155 mg of Compound TR-4099.

A. Compound TR-4098 had the following spectral properties:

Analysis -- IR: λ_(max) ^(CHCl).sbsp.3 2.78μ, 2.90μ, 5.75μ and 10.30μ

NMR(CDCl₃) δ3.67, singlet, 3H, CO₂ CH₃ δ4.05, multiplet, 2H, CHOH δ5.82,multiplet, 2H, trans-olefinic-H

Optical Rotation: [α]_(D) (CHCl₃, c 1.02): -55.4°.

B. Compound TR-4099 had the following spectral properties:

Analysis -- IR: λ_(max) ^(CHCl).sbsp.3 2.78μ, 2.90μ, 5.75μ and 10.30μ.

NMR(CDCl₃) δ3.67, singlet, 3H, CO₂ CH₃, δ 4.05, multiplet, 2H, CHOH,δ5.82, multiplet, 2H, trans-olefinic-H.

Optical Rotation: [α]_(D) (CHCl₃, c 1.00): -49.0°.

EXAMPLE 2

This example illustrates the preparation of other Prostaglandin E₁Analogues and Prostaglandin A₁ Analogues.

Repeating in a similar manner the procedure of Example 1, but replacing1-iodo-3-(1-ethoxyethoxy)-3-(bicyclo[3.2.0]hept-3-yl)-1E-propene with1-iodo-3-(1-ethoxyethoxy)-7-(bicyclo[3.2.1]oct-2-yl)-1E-heptene (seeExample 9) or1-iodo-3-(1-ethoxyethoxy)-7-(bicyclo[4.4.0]dec-2-yl)-1E-heptene (seeExample 10) yields the following PGE₁ and PGA₁ analogues.

A. Compound TR-4117 had the following spectral properties:

Analysis -- IR: λ_(max) ^(CHCl).sbsp.3 2.78μ, 2.90μ, 5.75μ and 10.30μ

NMR(CDCl₃): δ3.67, singlet, 3H, CO₂ CH₃ δ 4.1, multiplet, 2H, CHOHδ5.66, multiplet, 2H, trans-olefinic-H.

Optical Rotation: [α]_(D) (CHCl₃, c 0.94): -29.3°.

B. Compound TR-4116 had the following spectral properties:

Analysis -- IR: λ_(max) ^(CHCl).sbsp.3 2.78μ, 2.90μ, 5.75μ 10.30μ

NMR(CDCl₃): δ3.64, singlet, 3H, CO₂ CH₃ δ 4.1, multiplet, 2H, CHOHδ5.66, multiplet, 2H, trans-olefinic-H

Optical Rotation: [α]_(D) (CHCl₃, c 1.03): -21.0°.

Compounds TR-4119 and TR-4118, Prostaglandin A₁ analogues, are formed inthe preparation of Compounds TR-4117 and TR-4116 above as side productsby the treatment with 65:35 acetic acid-water.

C. Compound TR-4119 has the following spectral properties:

Analysis -- IR: λ_(max) ^(CHCl).sbsp.3 2.78μ, 2.88μ, 5.78μ, 5.88μ, 6.30μand 10.08μ

NMR(CDCl₃): δ3.67, singlet, 3H, CO₂ CH₃ δ 3.30, multiplet, 1H, C₁₂ -Hδ4.12, multiplet, 1H, C₁₂ -H δ5.60, multiplet, 2H, trans-olefinic-Hδ6.17 (dd, J=2.0, 5.0Hz, 1H, C₁₀ -H δ7.46 ppm (dd, J=2.0, 5.0Hz, 1H, C₁₁-H)

Optical Rotation: [α]_(D) (CHCl₃, c 1.40): +90.0°.

D. Compound TR-4118 had the following spectral properties:

Analysis: spectral similar in essential aspects as those of CompoundTR-4119 above.

Optical Rotation: [α]_(D) (CHCl₃, c 1.13): +94.7°.

E. Compound TR-4172 had the following spectral properties:

Analysis -- IR: λ_(max) ^(CHCl).sbsp.3 2.79-3.03μ, 3.42μ, 5.78μ

NMR(CDCl₃): δ0.5-3.0, multiplet, 41H δ3.75, singlet, 3H δ3.8-4.3,multiplet, 2H δ5.7, multiplet, 2H

Optical Rotation: [α]_(D) (CHCl₃, c 1.01): -34.08°.

F. Compound TR-4166 had the following spectral properties:

Analysis -- IR: λ_(max) ^(CHCl).sbsp.3 2.79-3.12μ, 3.40μ and 5.78μ

NMR(CDCl₃): δ0.6-2.8, multiplet, 41H δ3.75, singlet, 3H δ3.7-4.3,multiplet, 2H δ5.7, multiplet, 2H

Optical Rotation: [α]_(D) (CHCl₃, c 1.56): -21.1°.

EXAMPLE 3

This example illustrates the preparation of other Prostaglandin E₁analogues.

Repeating in a similar manner the procedure of Example 1, but replacingmethyl7-[3R-{3R-(tetrahydropyran-2-yloxy)-5-oxocyclopent-1-enyl]heptanoatewith1-tetrahydropyran-2-yloxy}-7-[3R-(tetrahydropyran-2-yloxy)-5-oxocyclopent-1-enyl]heptaneyields the following PGE₁ analogues.

A. Compound TR-4643 had the following spectral properties:

Analysis -- IR: λ_(max) ^(CHCl).sbsp.3 2.78μ, 3.13μ, 3.40μ, 3.5μ, 5.75μ,8.0μ, 9.35μ, and 10.31μ

NMR(CDCl₃): δ1.0 to 3.0, multiplet, 27H δ3.1, singlet, 3H δ3.66,triplet, J=5Hz, 2H δ4.1, multiplet, 2H δ5.83 ppm, multiplet, 2H.

MS(70eV)m/e:346(p-H₂ O) 328(p-2H₂ O) 318, 302, 275, 269(p-C₇ H₁₁)251(p-C₇ H₁₁ -H₂ O) 233(p-C₇ H₁₁ -2H₂ O)

Optical Rotation: [α]_(D) (CHCl₃, c 1.0): -43°.

B. Compound TR-4642 had the following spectral properties:

Analysis -- IR, NMR and MS similar in essential aspects as those ofCompound TR-4643 above.

Optical Rotation: [α]_(D) (CHCl₃, c 1.0): -28.4°.

EXAMPLE 4

This example illustrates the preparation of Prostaglandin 11-deoxy E₁analogues.

Repeating in a similar manner the procedure of Example 1, but replacingmethyl 7-[3R-(tetrahydropyran-2-yloxy)-5-oxocyclopent-1-enyl]heptanoatewith methyl 7-(5-oxocyclopent-1-enyl)heptanoate and performing thefollowing additional procedure, to hydrolyze the ester group, yields thefollowing 11-deoxy PGE₁ analogues.

Following substantially the procedure of Example 1 as modified aboveresults in the yield of 871 mg of a yellow oil. The yellow oil wasstirred with 12.0 ml of 1N NaOH and 12 ml of tetrahydrofuran for 18 hrat 25° C. The solvents were removed in vacuo and the residue wasdissolved in water. The water layer was extracted with ethyl acetate andthe ethyl acetate extracts were backwashed with water. The aqueous layerwas acidified with concentrated hydrochloric acid and extracted withether. The ether extracts were washed with aqueous saturated NaCl, driedover MgSO₄, filtered through diatomaceous earth, and the ether solventremoved in vacuo to yield 548 mg of oily yellow prisms. This materialwas chromatographed on 85:15 silicic acid: diatomaceous earth (Celite)using a benzene to ethyl acetate gradient elution to yield 88 mg ofCompound TR-4097 and 142 mg of Compound TR-4096.

A. Compound TR-4097 had the following spectral properties:

Analysis -- IR: λ_(max) ^(CHCl).sbsp.e 2.78μ, 2.7-4.2μ, 5.85μ, 5.79μ,and 10.03μ

NMR(CDCl₃): δ4.0, multiplet, 1H, CHOH δ5.66, multiplet, 2H,trans-olefinic-H δ7.0, broad singlet, 2H, CO₂ H, OH.

B. Compound TR-4096 had the following spectral properties:

Analysis -- IR: λ_(max) ^(CHCl).sbsp.3 2.78μ, 2.7-4.2μ, 5.85μ, 5.79μ,and 10.03μ

NMR(CDCl₃): δ3.98, multiplet, 1H, CHOH δ5.65, multiplet, 2H,trans-olefinic-H δ7.35, multiplet, 2H, CO₂ H, OH.

EXAMPLE 5

Repeating in a similar manner the procedures of Example 1 and 4, butreplacing1-iodo-3-(1-ethoxyethoxy)-3-(bicyclo[3.2.0]hept-3-yl)-1E-propene with1-iodo-3-(1-ethoxyethoxy)-7-(bicyclo[4.4.0]dec-2-yl)-1E-heptene yieldsthe following 11-deoxy PGE₁ analogues.

A. Compound TR-4189 had the following spectral properties:

Analysis -- IR: λ_(max) ^(CHCl).sbsp.3 3.41μ, 5.74μ and 5.79μ δ0.7-2.7,multiplet, 43H δ3.65, singlet, 3H δ4.1, multiplet, 1H δ5.5 ppm,multiplet, 2H.

B. Compound TR-4190 had the following spectral properties:

Analysis -- IR: λ_(max) ^(CHCl).sbsp.3 3.41μ, 5.74μ, and 5.79μ

NMR(CDCl₃): δ0.5-2.8, multiplet, 43H δ3.6, singlet, 3H δ4.5, multiplet,1H δ5.5 ppm, multiplet, 2H.

EXAMPLE 6

This example illustrates the preparation of Prostaglandin 11-deoxy-E₂analogues.

Repeating in a similar manner the procedures of Examples 1, 4, and 5,but replacing methyl 7-(5-oxocylopent-1-enyl)heptanoate with methyl7-(5-oxocyclopent-1-enyl)hept-5Z-enoate yields the following 11-deoxyPGE₂ analogues.

A. Compound TR-4101 had the following spectral properties:

Analysis - IR: λ_(max) ^(CHCl).sbsp.3 2.78μ, 2.7-4.2μ, 5.79μ, 5.85μ, and10.3μ.

NMR(CDCl₃): δ4.3, multiplet, 1H, CHOH δ5.39, multiplet, 2H.cis-olefinic, H δ5.66, multiplet, 2H, trans-olefinic-H δ7.20, singlet,2H, CO₂ H, OH.

B. Compound TR- 4102 had spectral properties which were similar inessential aspects as those of Compound TR-4101 above.

C. Compound TR-4173 had the following spectral properties:

Analysis - IR: λ_(max) ^(CHCl).sbsp.3 2.78μ, 3.39μ, 5.28μ and 5.81μ

NMR(CDCl₃): δ0.6-2.8, multiplet, 39H δ4.15, multiplet, 1H δ5.55,multiplet, 4H δ6.4 ppm, singlet, 2H.

D. Compound TR-4174 had the following spectral properties:

Analysis - IR: λ_(max) ^(CHCl).sbsp.3 2.78μ, 3.41μ, 5.28μ and 5.81μ

NMR(CDCl₃): δ0.6-2.7, multiplet, 39H δ4.9, multiplet, 1H δ5.4,multiplet, 4H δ5.4, multiplet, 4H δ6.25 ppm, singlet 2H.

EXAMPLE 7

This example illustrates the preparation of Prostaglandin9a-homo-11-deoxy-E₂ analogues.

Repeating in a similar manner the procedure of Examples 1 and 4, butreplacing1-iodo-3-(1-ethoxyethoxy)-3-(bicyclo[3.2.0]hept-3-yl)-1E-propene with1-iodo-3-(1-ethoxyethoxy)-7-(bicyclo[4.4.0]dec-2-yl)-1E-heptene and alsoreplacing methyl7-[3R-(tetrahydropyran-2-yloxy)-5-oxocyclopent-1-enyl]heptanoate withmethyl 7-[6-oxocyclohex-1-enyl]hept-5Z-enoate (see Example 13 forpreparation) yields the following 9a-homo-11-deoxy-PGE₂ analogues.

A. Compound TR-VIIa had the following spectral properties:

Analysis - IR: λCHCl.sbsp.max^(CHCl) ₃ 2.79μ, 2.90μ, 5.80μ and 10.30μ.

NMR(CDCl₃): δ3.66, singlet, 3H, CO₂ CH₃ δ 4.14, multiplet, 1H, CHOHδ5.42, multiplet, 2H, cis-olefinic-H δ5.74, multiplet, 2H,trans-olefinic-H.

B. Compound TR-VIIb had spectral properties which were similar inessential aspects as those of Compound TR-VIIa above.

EXAMPLE 8

This example illustrates the preparation of Prostoglandin F analogues.

A solution of 243 mg of TR-4099 (Example 1) in 25 ml of absolute ethanolwas stirred with ice bath cooling as 400 mg of sodium borohydride wasadded. The resultant mixture was stirred with cooling for 1.25 hr beforeit was quenched by the addition of water and then evaporated in vacuo toremove solvent. The resultant residue was dissolved in ethyl acetate andwashed with water. The wash solution was back extracted with ethylacetate twice. The combined ethyl acetate extracts were dried (MgSO₄)and evaporated in vacuo to yield a clear oil. This material waschromatographed on Woelm silica gel (0.032- 0.063 mm) using ethylacetate elution to yield 105 mg of Compound TR-4712 and 67 mg ofCompound TR-4711.

A. Compound TR-4712 had the following spectral properties:

Analysis - IR: λ_(max) ^(CHCl).sbsp.3 2.78μ, 2.90μ, 3.42μ, 5.80μ, 6.96μ,8.00μ and 10.33μ

NMR(CDCl₃): δ3.40, singlet, 3H, OH δ3.70, singlet, 3H, CO₂ CH₃ δ4.05,multiplet, 3H, CHOH δ5.77, multiplet, 2H, trans-olefinic-H

Optical Rotation: [α]_(D) (CHCl₃, c 1.0): -14.1°.

B. Compound TR-4711 had spectral properties similar in essential aspectsto those of Compound TR-VIIIa above. Optical Rotation: [α]_(D) (CHCl₃, c1.0): +13.7°.

EXAMPLE 9

This example illustrates a typical preparation of the intermediatecompound1-iodo-3RS-(1-ethoxyethoxy)-7-(bicyclo[3.2.1]oct-2-yl)-1-E-heptene.

A. Preparation of 5-(bicyclo[3.2.1]oct-2-ylidene) pentanoic acid.

A mixture of 3.92 g (93 mmol) of sodium hydride (57% oil dispersion) and30 ml of dry dimethylsulfoxide was heated at 70°-80° under nitrogenuntil gas evolution ceased (2.5 hr). The mixture was cooled, and 19.7 g(44.3 mmol) of 4-(carboxybutyl)triphenylphosphonium bromide (Aldrich No.15,794-5) was added, followed by 20 ml of dimethylsulfoxide. Theresulting deep red mixture was stirred for 45 min at room temperatureunder nitrogen before a solution of 5.0 g (40.2 mmol) ofbicyclo[3.2.1]octan-2-one (Aldrich No. 11,903-2) in 20 ml ofdimethylsulfoxide was added dropwise over 1.75 hr. The resulting mixturewas stirred for 16 hr at room temperature before it was quenched by theaddition of 125 ml of water. The resulting solution was extracted withthree 250 ml portions of ether/ethyl acetate-1:1 (V/V) to remove neutralby products. The remaining aqueous phase was acidified by the additionof 15 ml of concentrated hydrochloric acid and extracted with three 250ml portions of ether-hexane-1:1 (V/V). These combined acidicether-hexane extracts were dried (MgSO₄), and evaporated in vacuo toyield 6.0 g of crude 5-(bicyclo[3.2.1]oct-2-ylidene)-pentanoic acid asan oil. This oil was purified by chromatography on silica gel 60(elution with CHCl₃ containing 0.5 % formic acid) to yield 4.1 g (49%)of pure material as a colorless oil.

Analysis - IR: λ_(max) ^(CHCl).sbsp.3 5.78μ, 3.41μ and 2.86 to4.17μ(broad).

NMR(DCl₃) δ3.0, broad, 1H δ4.9, broad triplet, 1H.

B. Preparation of 5-(bicyclo[3.2.1]oct-2-yl) pentanoic acid.

A solution of 3.4 g (16.3 mmol) of5-(bicyclo[3.2.1]-oct-2-ylidene)pentanoic acid in 100 ml of absoluteethanol was hydrogenated at 50 psi over 300 mg of platinum oxide in aParr apparatus. After 1.5 hr hydrogen uptake became slow. After 4 hr thesystem was flushed with nitrogen, and the catalyst was removed byfiltration through diatomaceous earth filter aid (Celite). The filtratewas evaporated in vacuo to yield 3.25 g (96%) of quite pure5-(bicyclo[3.2.1]oct-2-yl)pentanoic acid as a colorless oil.

Analysis - IR: λ_(max) ^(CHCl).sbsp.3 5.85μ, 3.41μ and 4.17μ(broad)

NMR(CDCl₃): δ11.6, broad singlet, 1H.

C. Preparation of 1-chloro-7-(bicyclo[3.2.1]oct2-yl)-1E-hepten-3-one.

A solution of 7.2 g (32 mmol) of 5-(bicyclo[3.2.1]-oct-2-yl)pentanoicacid in 20 ml of thionyl chloride was left overnight at room temperatureunder nitrogen. The excess thionyl chloride and byproducts were removedby evaporation in vacuo. The resulting acid chloride (7.8 g) was used inthe following procedure. A 65 ml portion of carbon tetrachloride in aflask fitted with a gas addition tube, dropping funnel, and mechanicalstirrer was saturated at 0° with acetylene which had been passed throughan activated aluminum oxide trap followed by two concentrated sulfuricacid traps. A 5.2 g (40 mmol) portion of anhydrous aluminum chloride wasadded as acetylene was continuously bubbled through the mixture. Theabove acid chloride was added dropwise followed by a small amount ofcarbon tetrachloride rinse. Acetylene was bubbled through the resultingmixture for an additional 4 hr. The mixture was then quenched with 150ml of crushed ice and 75 ml of brine. The layers which resulted wereseparated. The aqueous layer was extracted with three 75 ml portions ofether. The combinned ether extracts were washed with 10% aqueous HClthree times, saturated aqueous sodium bicarbonate three times, dried(MgSO₄), and evaporated in vacuo to yield 8.8 g of residue which waschromatographed on silica gel (benzene elution) to give 3.2 g (37%) ofpure 1-chloro-7-(bicyclo[3.2.1]oct-2-yl)-1E-hepten-3-one:

Analysis - NMR(CDCl₃): δ2.5, broad t, J=6.5Hz, 2H δ6.48, doublet,J=13.5Hz, 1H δ7.28, doublet, J=13.5Hz, 1H.

D. Preparation of 1-iodo-7-(bicyclo[3.2.1]oct-2-yl)-1E-hepten-3-one.

A solution of 3.2 g (13 mmol) of1-chloro-7-bicyclo[3.2.1]oct-2-yl)-1E-heptene-3-one and 7.5 g (50 mmol)of sodium iodide in 25 ml of dry acetone (distilled from potassiumcarbonate) was refluxed for 18 hr under nitrogen. The solvent wasremoved in vacuo, and the residue was taken up in 50 ml of water andthen extracted three times with 30 ml portions of ether. The combinedether extracts were washed with aqueous sodium thiosulfate, dried(MgSO₄) and evaporate in vacuo to yield 3.8 g (88%) of1-iodo-7-(bicyclo[3.2.1]oct-2-yl)-1E-hepten-3-one.

Analysis - NMR(CDCl₃): δ2.5, broad t, J=6.7Hz, 2H δ7.08, doublet,J=15Hz, 1H δ7.78, doublet, J=15Hz, 1H.

E. Preparation of 1-iodo-7-(bicyclo[3.2.1]oct-2-yl)-1E-hepten-3RS-ol.

To a solution of 3.8 g (10.9 mmol) of1-iodo-7-(bicyclo[3.2.1]oct-2-yl)-1E-hepten-3-one in 50 ml of absoluteethanol under argon at 0° was added a slurry of 1.6 g (44 mmol) ofsodium borohydride in 50 ml of ethanol. The resulting mixture wasstirred for 1 hr, and the solvent was removed in vacuo. The residue wastaken up in 100 ml of water and extracted with three 100 ml portions ofether. The combined extracts were dried (MgSO₄) and evaporated in vacuoto yield 4.0 g (100%) of1-iodo-7-(bicyclo[3.2.1]-oct-2-yl)-1E-hepten-3RS-ol.

Analysis - IR: λ_(max) ^(CHCl).sbsp.3 10.65μ, 3.43μ, 2.91μ and 2.79μ

NMR(CDCl₃): δ4.1, broad, 1H δ6.15 to 6.75, complex, 2H.

F. Preparation of1-iodo-3RS-(1-ethoxyethoxy)-7-(bicyclo[3.2.1]oct-2-yl)-1E-heptene.

To a solution of 4.0 g (11 mmol) of1-iodo-7-(bicyclo[3.2.1]oct2-yl)-1E-hepten-3-ol in 15 ml of ethylvinylether was added two drops of phosphorus oxychloride. After standing for18 hr at room temperature the resulting solution was washed withsaturated aqueous sodium bicarbonate. The wash solutions was backextracted twice with ether. The combined ether extracts were washed oncewith saturated aqueous sodium chloride, dried (MgSO₄) and evaporated toyield a yellow oil. This yellow oil was chromatographed on silica gel(benezene elution) to yield 1.6 g of1-iodo-3RS-(1-ethoxyethoxy)-7-(bicyclo[3.2.1]oct-2-yl)-1E-heptene and1.0 g of the unprotected starting material which was recycled. Thespectrum of pure product was:

Analysis - NMR(CDCl₃): δ3.24 to 3.73, multiplet, 2H δ3.97, broad, 1Hδ4.67, quartet, J=5.3Hz, 1H δ6.08 to 6.65, multiplet, 2H.

EXAMPLE 10

This example illustrates a typical preparaton of1-iodo-3RS-(1-ethoxyethoxy)-7-(bicyclo[4.4.0]dec-2yl)-1E-heptene.

A. Preparation of 5-(bicyclo[4.4.0]dec-2-ylidene)-pentanoic acid.

Repeating in a similar manner the procedure of Example 9 above butreplacing bicyclo[3.2.1]octan-2-one with bicyclo[4.4.0]decan-2-one(1-decalone, Aldrich No. 15,506-3) yields the intermediate5-(bicyclo[4.4.0]dec-2-ylidene)pentanoic acid.

Analysis - NMR(CDCl₃): δ5.0, triplet, J=6.5Hz, 1H δ10.4, broad singlet,1H

B. Preparation of 5-(bicyclo[4.4.0]dec-2-yl)pentanoic acid.

Repeating in a similar manner the procedure of Example 9B above butreplacing 5-(bicyclo[3.2.1]oct-2-ylidene)-pentanoic acid with5-(bicyclo[4.4.0]oct-2-ylidene)-pentanoic acid yields the intermediate5-(bicyclo[4.4.0]dec-2-yl)pentanoic acid.

Analysis - NMR(CDCl₃): δ10.0, broad singlet, 1H

C. Preparation of 1-chloro-7-(bicyclo[4.4.0]dec-2-yl-1E-hepten-3-one.

Repeating in a similar manner the procedure of Example 9C above, butreplacing 5-(bicyclo[3.2.1]oct-2-yl)pentanoic acid with5-(bicyclo[4.4.0]dec-2-yl)pentanoic acid yields the intermediate1-chloro-7-(bicyclo[4.4.0]dec-2-yl)-1E-hepten-3-one.

Analysis - NMR(CDCl₃): δ2.5, broad triplet, J=6.5Hz, 2H δ6.4, doublet,J=13Hz, 1H δ7.3, doublet, J=13Hz, 1H

D. Preparation of 1-iodo-7-(bicyclo[4.4.0]dec-2-yl)-1E-hepten-3-one.

Repeating in a similar manner the procedure of Example 9D above, butreplacing 1-chloro-7-(bicyclo[3.2.1]oct-2-yl)-1E-hepten-3-one with1-chloro-7-(bicyclo[4.4.0]dec-2-yl)-1E-hepten-3-one yields theintermediate 1iodo-7-(bicyclo[4.4.0]dec-2-yl)-1E-hepten-3-one.

Analysis - NMR(CDCl₃): δ2.5, broad triplet, J=6.5Hz, 2H δ7.1, doublet,J=14Hz, 1H δ7.8, doublet, J=14Hz, 1H

E. Preparation of 1-iodo-7-(bicyclo[4.4.0]dec-2-yl)-1E-hepten-3RS-ol.

Repeating in a similar manner the procedure of Example 9E above, butreplacing 1-iodo-7-(bicyclo[3.2.1]oct-2-yl)-1E-hepten-3-one with1-iodo-7-(bicyclo[4.4.0]dec-2-yl)-1 E-heptene-3-one yields theintermediate 1-iodo-7-(bicyclo[4.4.0]dec-2-yl)-1E-hepten-3RS-ol.

Analysis - NMR(CDCl₃): δ4.17, multiplet, 1H δ6.0 to 7.0, multiplet, 2H

F. Preparation of1-iodo-3RS-(-ethoxyethoxy)-7-(bicyclo[4.4.0]dec-2-yl)-1E-heptene.

Repeating in a similar manner the procedure of Example 9F above, butreplacing 1-iodo-7-(bicyclo[3.2.1]oct-2-yl)-1E-hepten-3RS-ol with1-iodo-7-(bicyclo[4.4.0]dec-2-yl)-1E-hepten-3RS-ol yields theintermediate1iodo-3RS-(1-ethoxyethoxy)-7-(bicyclo[4.4.0]dec-2-yl)-1E-heptene.

Analysis - NMR(CDCl₃): δ3.5 to 4.2, multiplet, 3H δ4.8, multiplet, 1Hδ6.0 to 7.0, multiplet, 2H.

EXAMPLE 11 This example illustrates a typical preparation of1-iodo-3RS-(1-ethoxyethoxy)-3-(bicyclo[3.2.0]hept-3-yl)-1E-propene. A.Preparation of cis-1,2,-bis-(hydroxymethyl) cyclobutane.

A solution of 50.0 g (0.40 mmol) of cis-1,2-cyclobutane dicarboxylicanhydride (Aldrich No. 14,543-2) in 50 ml of ether and 75 ml of THF wasadded in small portions to a 0° C slurry of 21.0 g of lithium aluminumhydride in 210 ml of ether in a 500 ml three-necked round bottomed flaskequipped with a reflux condenser, mechanical stirring, addition funneland argon inlet. The reaction mixture was warmed to 50° C and stirredfor 1 hr. Ethyl acetate (51.0 ml) was added dropwise, followed by 21.0ml water, 21.0 ml 15% aqueous sodium hydroxide and 40 ml of water. Thereaction mixture was stirred for 18 hr at 25° C, then filtered. Thefiltrate was eashed with brine and vacuum distilled to afford 21.5 g ofcis-1,2-bis-hydroxymethyl)cyclobutane as a clear oil, bp 94°-97° (vacuumpump).

Analysis - IR: λ_(max) ^(CHCl).sbsp.3 2.78μ, 3.0μ(broad), 5.9μ

NMR(CDCl₃): δ1.10-2.30, multiplet, 4H, CH₂ -CH, δ2.65, multiplet, 2H,CH-CH δ3.60multiplet, 4H, CH₂ OH δ4.65, broad t, 2H, OH.

B. Preparation of cis-1,2-bis(bromoethyl)cyclobutane.

To 44 g of phosphorus tribromide (-10° C) was added dropwise 10.7 g ofdistilled cis-1,2-bis(hydroxymethyl)cyclobutane over a 1 hr period. Thereaction mixture was warmed to 25° C and stirred for 2 hr, then heatedto 80-85° for 18 hr. The reaction mixture was cooled in ice and coldwater added. The layers were separated and the aqueous layer wasextracted with methylene chloride. The organic extracts were combined,washed with 5% aqueous sodium carbonate and water, then distilled toyield 13.8 g of cis-1,2-bis(bromomethyl)cyclobutane as a purple oil, bp86° C (vacuum pump).

Analysis - IR: λ_(max) ^(CHCl).sbsp.3 3.4μ, 7.0μ, 8.1μ (no OH signalobserved)

NMR(CDCl₃): δ1.3-2.5, multiplet, 4H, CH₂ -CH₂ δ2.8, multiplet, 2H, CH-CHδ3.5, multiplet, 2H, CH₂ Br.

C. Preparation of 3,3-bis(ethoxycarbonyl)bicyclo[3.2.0]heptane.

In a 250 ml round-bottomed flask equipped with mechanical stirring,reflux condenser, addition funnel and argon inlet was placed 20.2 g ofcis-1,2-bis(bromomethyl)cyclobutane, 12.4 ml diethylmalonate, and 72 mlof dry t-butanol. The reaction mixture was refluxed and a solution of19.9 g of potassium-t-butoxide in 123 ml of t-butanol was added over 6.0hr. The reaction mixture was refluxed for 15 hr. The reaction mixturewas cooled by external application of an ice-water bath and an equalvolume of water added. The mixture was extracted with ether. The etherextracts were washed with 3 N hydrochloric acid and 5% aqueous sodiumbicarbonate, then dried (MgSO₄), filtered and distilled in vacuo toyield 10.3 g of 3,3-bis(ethoxycarbonyl)bicyclo[3.2.0]heptane as a clearoil, bp 100°-105° C (vacuum pump).

Analysis - IR: λ_(max) ^(CHCl).sbsp.3 5.85μ

NMR(CDCl₃): δ1.22, pair of t, J=7.0Hz, broad, CH₂ CH₃ δ4.37 quartet, 4H,CH₂ CH₃.

D. Preparation of bicyclo[3.2.0]heptane-3,3-dicarboxylic acid.

A solution of 10.3 g of 3,3-bis(ethoxycarbonyl)bicyclo[3.2.0]heptane in68 ml of 16% potassium hydroxide in 1:1 methanol-water was refluxed for16 hr under argon. The solvents were removed in vacuo and the residuedissolved in a minimum amount of water. The solution was acidified withconcentrated hydrochloric acid and the precipitated acid isolated byvacuum filtration to yield 6.9 g ofbicyclo[3.2.0]heptane-3,3-dicarboxylic acid as a white solid, mp161°-170°.

Analysis - NMR(DMSO-d₆): δ7.65, broad singlet, 2H, CO₂ H.

E. Preparation of cis-(bicyclo[3.2.0]hept-3-yl)carboxylic acid.

Bicyclo[3.2.0]heptane-3,3-dicarboxylic acid (6.90 g) was heated at 190°under argon for 1 hr to afford 4.75 g ofcis-(bicyclo[3.2.0]hept-3-yl)carboxylic acid as a brown oily solid.

Analysis - NMR(CDCl₃): δ10.18, broad singlet, 1H, CO₂ H IR(CHCl₃):2.75-4.4μ(broad), 5.85μ, 6.40μ.

F. Preparation of 1-chloro-3-(bicyclo[3.2.0]hept-3-yl)-1E-propen-3-one.

Repeating in a similar manner the procedure of Example 9C above, butreplacing 5-(bicyclo[3.2.1]oct-2-yl)pentanoic acid withbicyclo[3.2.0]heptane-3-carboxylic acid yields the intermediate1-chloro-3-(bicyclo[3.2.0]-hept-3-yl)-1E-propen-3-one.

Analysis - NMR(CDCl₃): δ6.66, doublet, J=14Hz, 1H δ7.36, doublet,J=14Hz, 1H.

G. Preparation of 1-iodo-3-(bicyclo[3.2.0]hept-3-yl)-1E-propen-3-one.

Repeating in a similar manner the procedure of 9D above, but replacing1-chloro-7-(bicyclo[3.2.1]oct-2-yl)-1E-hepten-3-one with1-chloro-3-(bicyclo[3.2.0]hept-3-yl)-1E-propen-3-one to yield theintermediate 1-iodo-3-(bicyclo[3.2.0]hept-3-yl)-E-propen-3-one.

Analysis - NMR(CDCl₃): δ7.27, doublet, J=15Hz, 1H δ7.99, doublet,J=15Hz, 1H

H. Preparation of 1-iodo-3-(bicyclo[3.2.0]hept-3-yl)-1E-propen-3RS-ol.

Repeating in a similar manner the procedure of 9E above, but replacing1-iodo-7-(bicyclo[3.2.1]oct-2-yl)-1E-hepten-3-one with1-iodo-3-(bicyclo[3.2.0]hept-3-yl)-1E-propen-3-one yields theintermediate 1-iodo-3-(bicyclo[3.2.0]-hept-3-yl)-1E-propen-3RS-ol.

Analysis - NMR(CDCl₃): δ4.2, multiplet, 1H δ6.26, doublet, J=15Hz,1Hδ6.62, doublet of doublets, J=15 and 6Hz, 1H.

I. Preparation of1-iodo-3RS-(1-ethoxyethoxy)-3-(bicyclo[3.2.0]hept-3-yl)-1E-propane.

Repeating in a similar manner the procedure of 9F above, but replacing1-iodo-7-(bicyclo[3.2.1]oct-3-yl)-1E-hepten-3RS-ol with1-iodo-3-(bicyclo[3.2.0]hept-3-yl)-1E-propen-3RS-ol yields theintermediate1-iodo-3RS-(1-ethoxyethoxy)-3-(bicyclo[3.2.0]hept-3-yl)-1E-propene.

Analysis - NMR(CDCl₃): δ3.5 to 4.2, multiplet, 3H δ4.8, multiplet, 1Hδ6.0 to 7.0, multiplet, 2H.

EXAMPLE 12

This example illustrates a typical preparation of1-iodo-3RS-(1-ethoxyethoxy)-4-(bicyclo[2.2.1]hept-2-yl)-1E-butene.

A. Preparation of 1-chloro-4-(bicyclo[2.2.1]hept-2-yl)-1E-propen-3-one.

Repeating in a similar manner the procedure of Example 9C abovereplacing 5-(bicyclo[3.2.1]oct-2-yl)pentanoic acid with(bicyclo[3.2.1]hept-2-yl)acetic acid (Aldrich No. 12,7264) yields theintermediate 1-chloro-4-(bicyclo[2.2.1]hept-2-yl-1E-propen-3-one.

Analysis - NMR(CDCl₃): δ6.2, doublet, J=13Hz, 1H δ6.95, doublet, J=13Hz,1H.

B. Preparation of 1-iodo-4-(bicyclo[2.2.1]hept-2-yl)-1E-propen-3-one.

Repeating in a similar manner the procedure of Example 9D above butreplacing 1-chloro-7-(bicyclo[3.2.1]oct-2-yl)-hept-2-yl)-1E-propen-3-onewith 1-chloro-4-(bicyclo[2.2.1]-hept-2-yl)-1E-propen-3-one yields theintermediate 1-iodo-4-(bicyclo[2.2.1]hept-2-yl)-1E-propen-3-one.

Analysis - NMR(CDCl₃): δ7.20, doublet, J=15Hz, 1H δ7.85, doublet,J=15Hz, 1H.

C. Preparation of 1-iodo-4-(bicyclo[2.2.1]hept-2-yl)-1E-propen-3RS-ol.

Repeating in a similar manner the procedure of Example 9E above, butreplacing 1-iodo-7-(bicyclo[3.2.1]oct-2-yl)-1E-hepten-3-one with1-iodo-4-(bicyclo[2.2.1]hept-2-yl)-1E-propen-3-one yields theintermediate 1-iodo-4-(bicyclo[2.2.1]hept-2-yl)-1E-propen-3RS-ol.

Analysis - NMR(CDCl₃): δ5.04, multiplet, 1H δ6.1 to 6.8, multiplet, 2H.

D. Preparation of1-iodo-3RS-(1-ethoxyethoxy)-4-(bicyclo[2.2.1]hept-2-yl)-1E-butene.

Repeating in a similar manner the procedure of Example 9F above, butreplacing 1-iodo-7-(bicyclo[3.2.1]oct-2-yl)-1E-hepten-3RS-ol with1-iodo-4-(bicyclo[2.2.1]hept-2-yl)-1E-propen-3RS-ol yields theintermediate1-iodo-3RS-(1-ethoxyethoxy)-4-(bicyclo[2.2.1]hept-2-yl)-1E-butene.

Analysis - NMR(CDCl₃): δ3.5, multiplet, 3H δ4.7, multiplet, 1H δ6.1 to6.6, multiplet, 2H.

EXAMPLE 13

This example illustrates a typical preparation of methyl7-(6-oxocyclohex-1-enyl)hept-5Z-enoate.

A. Preparation of 7-oxabicyclo[4.3.0]non-2-en-8-one.

This compound was prepared by following the procedures of E. J. Coreyand T. Ravindranathan, Tetrahedron Letters, 4753 (1971).

A solution of 13.8 g of the above compound in 100 ml of dry methylenechloride (passed through Woelm activity grade I alumina prior to use)was stirred at -78° under argon as 19.0 ml (107 mmol) ofdiisobutylaluminum hydride was added dropwise over 0.5 hr. After 3 hr at-78° the reaction mixture was quenched at -78° by the slow addition ofseveral ml of 10% aqueous hydrochloric acid. The resultant mixture wasdiluted with 200 ml of methylene chloride. The mixture was then stirredin an ice-water bath as 100 ml of 10% hydrochloric acid was addeddropwise. The layers which formed were separated and the aqueous phasewas extracted twice more with methylene chloride. The combined methylenechloride extracts were washed with brine and then with saturated aqueoussodium bicarbonate. The washed extract was dried (Na₂ SO₄) andevaporated in vacuo to yield 12.3 g of 7-oxabicyclo[4.3.0]non-2-en-8-ol.

Analysis - IR: λ_(max) ^(CHCl).sbsp.3 14.3μ, 13.7μ, 10.87μ, 9.90μ,9.61μ, 9.27μ, 6.90μ, 3.40μ and 2.78 to 3.13(broad)

NMR(CDCl₃): δ1.0 to 3.0, multiplet, 7H δ4.0 to 4.8, multiplet, 2H δ5.2to 6.0, multiplet, 3H.

B. Preparation of 7-(6-hydroxycyclohex-2-enyl)hept-5Z-enoic acid.

A 12.5 g (296 mmol) portion of sodium hydride (57% oil dispersion) washeated with 95 ml of dry dimethylsulfoxide (DMSO) under argon at 65°-75°for ca. 2.5 hr until hydrogen evolution had ceased. The mixture wasstirred with ice-water cooling as 48.3 g (109 mmol) of4-carboxybutyltriphenylphosphonium bromide (Aldrich) was added as asolid. The resultant deep red mixture was stirred at 0° for severalminutes, then at room temperature until most of the salts had dissolved(1 hr.). A solution of 12.2 g (87.1 mmol) of7-oxabicyclo[4.3.0]non-2-en-8-ol in 10 ml of dry DMSO was added dropwiseover 2 hr to the vigorously stirred ylide solution. The resultant darkmixture was stirred for 20 hr at room temperature. Water (200 ml) wasadded then and the resultant mixture was extracted three times withethyl acetate and these extracts were discarded. The remaining aqueousphase was acidified with concentrated hydrochloric acid and thenextracted four times with ethyl acetate. The combined extracts weredried (MgSO₄) and evaporated in vacuo. The resultant residue wasevaporated at 0.1 mm as the pot was warmed to 50° and the receiver flaskwas cooled in an acetone-dry bath. The yield of crude orange oil was32.5 g (theoretical yield 19.5 g) and contained in addition to thedesired product, considerable aromatic byproduct as evidenced from annmr spectrum of this oil. This oil was extracted several times with warmether-pentane (1:1). The combined extracts were dried (MgSO₄) andevaporated in vacuo to give 11.9 g of7-(6-hydroxycyclohex-2-enyl)hept-5Z-enoic acid. A portion of thisproduct was purified by column chromatography on silicic acid-Celite(85:15) using benzene to ethyl acetate gradient elution to obtain pure7-(6-hydroxycyclohex-2-enyl)hept-5Z-enoic acid.

Analysis - IR: λ_(max) ^(CHCl).sbsp.3 9.35μ, 8.08μ, 7.10μ, 6.95μ, 5.85μ,3.40μ and 2.78μ to 4.17μ(broad)

NMR(CDCl₃): δ1.1 to 2.8, multiplet, 13H δ2.1, multiplet, 1H δ5.2 to 6.3,multiplet, 6H

Mass Spectrum (70 eV): m/e 224, 220, 206, 147, 133, 127, 119, 105, 97,91, 80, 79(base), 67 and 55.

C. Preparation of 7-(6-oxocyclohex-2-enyl)hept-5Z-enoic acid.

A solution of 15.8 g of 7-(6-hydroxycyclohex-2-enyl)-hept-5Z-enoic acid(as obtained by ether-pentane extraction as described above) in 300 mlof acetone was stirred with ice-bath cooling as 30 ml of standard Jonesreagent was added dropwise. The resultant mixture was stirred for 10 minat 0° and then quenched by the addition of several ml of isopropylalcohol. After stirring for another 10 min at 0° the solvents wereremoved by evaporation in vacuo. The residue was dissolved in water andextracted several times with ether. The combined ether extracts werewashed with brine, dried (MgSO₄) and evaporated in vacuo to yield 13.0 gof crude 7-(6-oxocyclohex-2-enyl)hept-5Z-enoic acid as a yellow oil.

Analysis - IR: λ_(max) ^(film) 952μ, 8.07μ, 7.09μ, 6.95μ, 5.85μ, 3.40μ,3.37μ and 2.78μ to 4.17μ(broad)

NMR(CDCl₃): δ1.3 to 3.2, multiplet, 13H δ5.2 to 6.2, multiplet, 4H δ8.5,broad singlet, 1H.

D. Preparation of Methyl 7-(6-oxyocyclohex-1-enyl)-hept-5Z-enoate.

A solution of 13.0 g of crude 7-(6-oxocyclohex-2-enyl)hept-5Z-enoic acidin 200 ml of dry methanol was stirred under argon as 2 ml of acetylchloride was added. The resultant yellow solution was left to stand for2.6 days (on another occasion 16 hr was found to be sufficient). Solventwas removed by evaporation in vacuo and the residue was dissolved inether and washed with saturated aqueous sodium bicarbonate. The washsolution was back extracted with ether. The combined ether extracts weredried (MgSO₄) and evaporated in vacuo to yield 11.6 g of crude methyl7-(6-oxocyclohex-1-enyl)hept-5Z-enoate as a yellow oil. This product waspurified by chromatography on silicic acid-Celite (85:15) using benzeneto ethyl acetate gradient elution to give 0.78 g of ca. 80% purematerial and 8.41 g of pure material.

Analysis - IR: λ_(max) ^(film) 9.17μ, 8.55μ, 8.33μ, 8.00μ, 7.30μ, 7.04μ,5.95μ, 5.74μ and 3.39μ

NMR(CDCl₃): δ1.3 to 2.5, multiplet, 12H δ2.9, multiplet, 2H δ3.67,singlet, 3H δ5.45, multiplet, 2H δ6.7, multiplet, 1H.

EXAMPLE 14 A. Evaluation of Inhibition of Human Platelet Aggregation byAnalogues of Prostaglandins Structure III.

The ability of test compounds to inhibit platelet aggreagation wasdetermined by a modification of the turbidometric technique of Born(Nature, 194: 927 [1962]). Blood was collected from human volunteer whohad not ingested aspirin or aspirin-containing products within thepreceding two weeks in heparinized containers and was allowed to settlefor one (1) hour. The platelet rich plasma (prp) supernates werecollected and cooled. Siliconized glassware was used throughout.

In a representative assay 1.9 ml of PRP and 0.2 ml of test compound atthe appropriate concentrations (0.001 to 100 mcgm), or 0.2 ml ofdistilled water (control procedure) were placed in sample cuvettes. Thecuvettes were placed in a 37° C incubation block for 15 minutes, andthen in a spectrophotometer linked to a strip chart recorder. After30-60 seconds, 0.2 ml of a solution, prepared by diluting a calf-skincollagen solution 1:9 with Tyrodes' Solution, was added to each cuvette.Platelet aggregation was evidenced by a decrease in optical density.

Calculation of the degree of inhibition of platelet aggregationexhibited by each concentration of test compound was accomplishedaccording to the method of Caprino et al., (Arzneim-Forsch., 23:1277[1973]). An ED₅₀ value was then determined graphically. Activity of thecompounds was scored as follows:

    ______________________________________                                        ED.sub.50 (mcg/kg)   Activity Value                                           ______________________________________                                        No activity          0                                                        >1.0                 1                                                        >0.1≦1.0      2                                                        >0.01≦0.1     3                                                        >0.001≦0.01   4                                                        ≦0.001        5                                                        ______________________________________                                    

B. Evaluation of the Effects of Prostaglandin Analogues III on GastricSecretion in the Rat.

A procedure based on that described by Lipmann (J. Pharm. Pharmacol.,21:335 [ 1968]) was used to assess the influence of test compounds ongastric secretion. Rats of one sex weighing 150 to 200 g were randomlydivided into groups of six animals each and fasted for 48 hourspreviously to the experiments, water being available adlibitum. Theanimals were anesthetized with ether, the abdomen was opened through amidline incision and the pylorus was ligated. Test compounds werediluted from stock solution so as to administer a dose of 1.5 mg/kg in avolume equivalent to 1 ml/kg. Subcutaneous injections were appliedimmediately after surgery and again 2 hours later, so that a total doseof 3.0 mg/kg was administered. Dilutions were made with phosphate buffer(pH 7.38) as recommended by Lee et al. (Prostaglandins 3:29 [ 1973]), inorder to insure adequate stability of drugs at the subcutaneous depot.Each compound was tested in one group of rats; an additional controlgroup received only the vehicle.

Four hours after pyloric ligation the animals were killed with ether,the cardias ligated and the stomachs removed. The volume of gastricsecretion was measured and the contents centrifuged at 5000 rpm for 10minutes. Total acid in the supernatant was titrated against a 0.1 Nsodium hydroxide solution and the amount expressed in mEq.

Volume and total acid values of the treated group were compared withthose of the controls by the "T" test. Antisecretory activity was scoredaccording to the following scale:

    ______________________________________                                        % decrease in acidity                                                                              Activity Value                                           ______________________________________                                        <26                  0                                                        26-50, not significant                                                                             1                                                        26-50, significant   2                                                        51-75                3                                                        76-100               4                                                        ______________________________________                                    

C. Evaluation of the Effects of Prostaglandin Analogues III on FemoralBlood Flow in the Dog.

The peripheral vasodilator or constrictor effects of test compounds weredetermined in mongrel dogs of either sex, weighing between 10 and 20 kganesthestized intravenously with 35 mg/kg of sodium pentobarbital. Anexternal iliac artery was dissected immediately above the femoral archfor a length of approximately 5 cm and a previously calibrated,non-connulating electromagnetic flowmeter sensor with a lumen between2.5 and 3.5 mm was placed snugly around the vessel. Cannulas were placedin a branch of the artery arising distally to the location of theflowmeter sensor for intraarterial drug administrations, in thecontralateral femoral artery for systemic blood pressure recordings andin the trachea for artificial respiration with room air. Femoral bloodflow and systemic blood pressure were continuously recorded with anelectromagnetic flowmeter and pressure tranducer, respectively.

After an adequate control period, test compounds were injectedintraarterially at one log-spaced doses ranging from 0.001 to 10 mcg.,in a volume of 0.5 ml and at 5 to 10 minute intervals. Maximum changesin bloodflow, as well as any variations in blood pressure, weretabulated for each dose in absolute values (ml/min. and mmHg). Thecalculations were made taking as control values those existingimmediately before administration of each dose. The direction of theobserved change (plus for increase and minus for decrease) was alsonoted. The dose changing bloodflow by 100 ml/min (ED₁₀₀ ml/min) wascalculated graphically and was used for scoring activity as follows:

    ______________________________________                                        ED.sub.100 ml/min, mcg                                                                             Activity Value                                           ______________________________________                                        >10.0                0                                                        1.01 - 10.0          1                                                        0.11 - 1.0           2                                                        0.01 - 0.1           3                                                        ______________________________________                                    

D. Evaluation of the Effects of Prostaglandin Analogues III on BloodPressure and Heart Rate in the Anesthetized Cat.

The acute effects of test compounds on blood pressure and heart ratewere determined in cats of either sex anesthetized with a mixture ofpentobarbital sodium (35 mg/kg, i.v.) and barbital sodium (100 mg/kg,i.v.). Cannulas were placed in the trachea to allow adequate spontaneousventilation, in a femoral artery for blood pressure recording with astrain gage transducer, and in a saphenous vein for drug administration.Heart rate was recorded by means of a cardiotachometer driven by the Rwave of the electrocardiogram. After a period of 10 minutes of stablerecordings of blood pressure and heart rate, the test compound wasadministered intravenously at doses increasing from 0.01 to 10.0 mcg/kg,spaced one log and injected at 10 minutes intervals. All doses wereinjected in a volume of 0.1 ml/kg. Modifications of blood pressure andheart rate induced by the test compound were expressed both in absoluteunits (mmHg and beats/minutes) and as percent of values recordedimmediately before administration of each dose. Biphasic responses weretabulated in the order in which they occur. The direction of theobserved changes was also noted (+ for increases and - for decreases).

Activity of compounds in this test was judged only on the basis of thedegree of hypotension observed. Thus, the ED₅₀ mmHg (dose decreasingblood pressure by 50 mmHg) was calculated graphically and the compoundscored according to the following scale:

    ______________________________________                                        ED.sub.50 mmHg, mcg/kg                                                                             Activity Value                                           ______________________________________                                        >10.0                0                                                        1.01 - 10.0          1                                                        0.11 - 1.0           2                                                        0.01 - 0.1           3                                                        ______________________________________                                    

Table D summarizes the results of the preceding assays utilizing thepreferred examples.

TABLE D

Summary of Activity of Prostaglandin Analogues III in; Test A:Inhibition of Human Platelet Aggregation; Test B: Inhibition of RodentGastric Secretion; Test C: Increase in Canidae Femoral Blood Flow; andTest D: Decrease in Normal Feline Blood Pressure and Heart Rate

    ______________________________________                                        TR    Example  Activity Value                                                 No.   No.      Test A   Test B Test C Test D                                  ______________________________________                                        4118  2D       1        0      0      0                                       4119  2C       1        0      0      0                                       4098  1A       5        4      2      2                                       4099  1B       2        1      0      0                                       4116  2B       1        0      0      0                                       4117  2A       1        0      0      0                                       4166  2F       1        0      0      0                                       4172  2E       1        0      0      0                                       4096  4B       1        0      2      0                                       4097  4A       1        2      1      0                                       4189  5A       1        0      NT     NT                                      4190  5B       1        0      NT     NT                                      4101  6A       1        1      3      1                                       4102  6B       1        4      2      0                                       4173  6C       1        NT     NT     NT                                      4174  6D       1        NT     NT     NT                                      4711  8B       NT       1      NT     NT                                      4712  8A       NT       2      NT     NT                                      ______________________________________                                         NT: Not tested                                                           

What is claimed is:
 1. A compound having the formula ##STR37## wherein gis an integer having a value of from 0 to 10;D is a R-hydroxymethyleneor S-hydroxymethylene radical; T is a hydroxymethyl radical; and B is abicycloalkyl radical of the formula ##STR38## where m and p are integershaving a value of from 1 to 4; n is an integer having a value of from 0to 4 such that n is not 1 when m and p are both 2; and the sum of m, nand p is greater than or equal to 3 and where the point of attachment ofthe alkyl chain (CH₂)_(g) to the bicycloalkyl radical is in the(CH₂)_(m) bridge or bridgehead position.
 2. A compound according toclaim 1, wherein m has a value of 3 or 4 and n has a value of 0 or
 1. 3.A compound according to claim 1, wherein g has a value of from 0 to 4; mhas a value of 3 or 4, n has a value of 0 or 1; and p has a value offrom 2 to
 4. 4. A compound according to claim 1, wherein the compound is7-{3R-hydroxy-5-oxo-2R-[3S-hydroxy-3-(bicyclo[3.2.0]hept-3-yl)-1E-propenyl]cyclopent-1R-yl}heptan-1-ol.5. A compound according to claim 1, wherein the compound is7-{3R-hydroxy-5-oxo-2R-[3R-hydroxy-3-(bicyclo[3.2.0]hept-3-yl)-1E-propenyl]cyclopent-1R-yl}heptan-1-ol.